US7196091B2 - Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them - Google Patents

Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them Download PDF

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US7196091B2
US7196091B2 US10/860,453 US86045304A US7196091B2 US 7196091 B2 US7196091 B2 US 7196091B2 US 86045304 A US86045304 A US 86045304A US 7196091 B2 US7196091 B2 US 7196091B2
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group
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oxo
amino
oxazolidin
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US20050014772A1 (en
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Frank Himmelsbach
Rainer Soyka
Birgit Jung
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Boehringer Ingelheim International GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the present invention relates to bicyclic heterocycles of general formula
  • diseases particularly tumoral diseases, as well as benign prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract and the preparation thereof.
  • BPH benign prostatic hyperplasia
  • R a denotes a hydrogen atom or a C 1-3 -alkyl group
  • R b denotes a phenyl or 1-phenylethyl group, wherein the phenyl nucleus is substituted in each case by the groups R 1 to R 3 , while
  • R a denotes a hydrogen atom
  • R b denotes a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluoro-phenyl or a 3-ethynylphenyl group,
  • R c denotes a (2-hydroxypropyl)amino or N-(2-hydroxypropyl)-N—(C 1-3 -alkyl)-amino group
  • R d denotes a hydrogen atom
  • X denotes a nitrogen atom
  • n denotes the number 2 or 3
  • R a denotes a hydrogen atom
  • R b denotes a 3-chloro-4-fluoro-phenyl group or 3-ethynylphenyl group
  • R c denotes a (2-hydroxypropyl)amino group
  • R d denotes a methoxy, ethyloxy or 2-methoxyethyloxy group
  • X denotes a nitrogen atom
  • n denotes the number 2
  • the compounds of general formula I may be prepared by the following methods, for example:
  • R a , R b , R d and X are as hereinbefore defined, with a compound of general formula Z 1 —(CH 2 ) n —R c (III), wherein
  • R c and n are as hereinbefore defined and Z 1 denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.
  • a halogen atom e.g. a chlorine or bromine atom
  • a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.
  • the reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone, optionally in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20° C. and 160° C.
  • a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as e.g.
  • triphenylphosphine/diethyl azodicarboxylate conveniently in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, dioxane, toluene or ethyleneglycol diethylether at temperatures between ⁇ 50 and 150° C., but preferably at temperatures between ⁇ 20 and 80° C.
  • R c , R d and n are as hereinbefore defined, with a halogenating agent, for example an acid halide such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride to obtain an intermediate compound of general formula (V),
  • a halogenating agent for example an acid halide such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride
  • R c , R d and n are as hereinbefore defined and Z 2 denotes a halogen atom such as a chlorine or bromine atom, and subsequent reaction with a compound of general formula R a —NH—R b (VI), wherein R a and R b are as hereinbefore defined.
  • the reaction with the halogenating agent is optionally carried out in a solvent such as methylene chloride, chloroform, acetonitrile or toluene and optionally in the presence of a base such as N,N-diethylaniline or N-ethyl-diisopropylamine at temperatures between 20° C. and 160° C.
  • a solvent such as methylene chloride, chloroform, acetonitrile or toluene
  • a base such as N,N-diethylaniline or N-ethyl-diisopropylamine at temperatures between 20° C. and 160° C.
  • the reaction is carried out with thionyl chloride and catalytic quantities of dimethylformamide at the boiling temperature of the reaction mixture.
  • reaction of the compound of general formula (V) with a compound of general formula (VI) is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide, optionally in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20° C. and 160° C.
  • a solvent such as ethanol, isopropanol, acetonitrile, dioxane or dimethylformamide
  • a base such as potassium carbonate or N-ethyl-diisopropylamine
  • R a , R b , R d , X and n are as hereinbefore defined
  • Z 3 denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, a sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group, with a compound of general formula H—R c (VIII), wherein R c is as hereinbefore defined.
  • reaction is conveniently carried out in a solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone, optionally in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20° C. and 160° C.
  • solvent such as ethanol, isopropanol, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone
  • R c denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups
  • this may be converted by hydrolysis, for example by hydrolysis in the presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, into a compound wherein R c denotes a (2-hydroxyethyl)amino group, wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is optionally substituted by one or two C 1-3 -alkyl groups, and/or
  • R c denotes a (2-hydroxyethyl)amino group, wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is optionally substituted by one or two C 1-3 -alkyl groups
  • this may be converted by reacting with a derivative of carbonic acid, for example phosgene, N,N′-carbonyldiimidazole or diphenyl carbonate, into a compound wherein R c denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups
  • a compound of general formula I is obtained which contains an amino, alkylamino or imino group this may be converted by alkylation or reductive alkylation, for example using formaldehyde or acetaldehyde and sodium triacetoxyborohydride, into a corresponding alkyl compound of general formula I.
  • R a , R b , R d and n are as hereinbefore defined and R e and R f independently of one another denote hydrogen atoms or C 1-3 -alkyl groups.
  • R e and R f independently of one another denote hydrogen atoms or C 1-3 -alkyl groups.
  • Compounds of this kind are described in WO 02/18351.
  • the 2-oxomorpholine ring is synthesised by reacting the above-mentioned starting compounds with reactive acetic acid derivatives, for example with an ⁇ -haloacetate such as methyl ⁇ -bromoacetate.
  • the compounds of general formula (IX) are prepared by reacting the above-mentioned starting compounds, conveniently in a solvent such as acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone, optionally in the presence of a base such as potassium carbonate or N-ethyl-diisopropylamine, at temperatures between 20° C.
  • a solvent such as acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide or N-methylpyrrolidinone
  • any reactive groups present such as hydroxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.
  • Protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
  • Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120° C., preferably at temperatures between 10 and 100° C.
  • an aqueous solvent e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100° C., but preferably at ambient temperatures between 20 and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
  • a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • a trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120° C. or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50° C.
  • an acid such as hydrochloric acid
  • a solvent such as acetic acid at temperatures between 50 and 120° C.
  • sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50° C.
  • the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore.
  • cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
  • the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • the enantiomers are preferably separated by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • Optically active acids in common use are e.g.
  • An optically active alcohol may be for example (+) or ( ⁇ )-menthol and an optically active acyl group in amides, for example, may be a (+)-or ( ⁇ )-menthyloxycarbonyl.
  • the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the compounds of general formulae II to VIII used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf. Examples I to XVI), optionally with additional inclusion of protecting groups.
  • the starting compounds for the compounds of general formula I according to the invention wherein X denotes a nitrogen atom and R c denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups may be obtained according to the following synthesis plan:
  • R d and Z 3 are as hereinbefore defined and R 10 and R 11 , which may be identical or different, denote hydrogen atoms or C 1-3 -alkyl groups.
  • R 10 and R 11 which may be identical or different, denote hydrogen atoms or C 1-3 -alkyl groups.
  • benzyl group mentioned as a protective group in the 3 position of the 3,4-dihydro-4-oxo-quinazoline group it is also possible to use other protective groups such as the 4-methoxybenzyl, 2,4-dimethoxybenzyl, methoxymethyl, benzyloxymethyl, (2-methoxyethyl)oxymethyl, (2-trimethylsilylethyl)oxymethyl or the pivaloyloxymethyl group.
  • the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or tyrosine kinase itself. It is also possible to block the transmission of signals to components located further downstream.
  • EGF-R Epidermal Growth Factor receptor
  • EGF-receptor kinase The inhibition of human EGF-receptor kinase was determined using the cytoplasmatic tyrosine kinase domain (methionine 664 to alanine 1186, based on the sequence published in Nature 309 (1984), 418). To do this, the protein was expressed in Sf9 insect cells as a GST fusion protein using the Baculovirus expression system.
  • the enzyme activity was measured in the presence or absence of the test compounds in serial dilutions.
  • the polymer pEY (4:1) produced by SIGMA was used as the substrate.
  • Biotinylated pEY (bio-pEY) was added as the tracer substrate. Every 100 ⁇ l of reaction solution contained 10 ⁇ l of the inhibitor in 50% DMSO, 20 ⁇ l of the substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 ⁇ g/ml bio-pEY) and 20 ⁇ l of enzyme preparation.
  • the enzyme reaction was started by the addition of 50 ⁇ l of a 100 ⁇ M ATP solution in 10 mM magnesium chloride.
  • the dilution of the enzyme preparation was adjusted so that the incorporation of phosphate into the bio-pEY was linear in terms of time and quantity of enzyme.
  • the enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% Triton X-100, 1 mM DTT and 10% glycerol.
  • the enzyme assays were carried out at ambient temperature over a period of 30 minutes and were ended by the addition of 50 ⁇ l of a stopping solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 ⁇ l were placed on a streptavidin-coated microtitre plate and incubated for 60 minutes at ambient temperature. Then the plate was washed with 200 ⁇ l of a washing solution (50 mM Tris, 0.05% Tween 20). After the addition of 100 ⁇ l of a HRPO-labelled anti-PY antibody (PY20H Anti-PTyr:HRP produced by Transduction Laboratories, 250 ng/ml) it was incubated for 60 minutes.
  • a stopping solution 250 mM EDTA in 20 mM HEPES pH 7.4
  • 100 ⁇ l were placed on a streptavidin-coated microtitre plate and incubated for 60 minutes at ambient temperature. Then the plate was washed with 200 ⁇ l of a washing solution (
  • microtitre plate was washed three times with 200 ⁇ l of washing solution.
  • the data were matched using an iterative calculation using an analytical programme for sigmoidal curves (Graph Pad Prism Version 3.0) with variable Hill pitch. All the iteration data released showed a correlation coefficient of more than 0.9 and the upper and lower values of the curves showed a spread of at least a factor of 5.
  • the concentration of active substance which inhibits the activity of EGF-receptor kinase by 50% (IC 50 ) was derived from the curves.
  • the compounds according to the invention had IC 50 values of less than 10 ⁇ M.
  • the compounds of general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases.
  • tyrosine kinases e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
  • the compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, e.g. in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
  • inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ 1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary
  • the compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Ménétrier's disease, secreting adenomas and protein loss syndrome.
  • diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Ménétrier's disease, secreting adenomas and protein loss syndrome.
  • the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat other diseases caused by abnormal function of tyrosine kinases, such as e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of haematopoietic cells, the treatment of nasal polyps, etc.
  • tyrosine kinases e.g. epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system, hyperproliferation of haematopoietic cells, the treatment of nasal polyps, etc.
  • the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastine), compounds which interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies, etc.
  • topoisomerase inhibitors e.g. etoposide
  • mitosis inhibitors e.g. vinblastine
  • nucleic acids e.g. cis-platin, cyclophosphamide, adriamycin
  • hormone antagonists e.g. tamoxif
  • these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic (e.g. ambroxol, N-acetylcysteine), broncholytic (e.g. tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and/or anti-inflammatory activity (e.g. theophylline or glucocorticoids).
  • a secretolytic e.g. ambroxol, N-acetylcysteine
  • broncholytic e.g. tiotropium or ipratropium or fenoterol, salmeterol, salbutamol
  • anti-inflammatory activity e.g. theophylline or glucocorticoids
  • these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion. These combinations may be administered either simultaneously or sequentially.
  • These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.
  • the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01–100 mg/kg of body weight, preferably 0.1–15 mg/kg.
  • they are formulated with one or more conventional inert carriers and/or diluents, e.g.
  • R c denotes a (2-hydroxyethyl)amino group wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is optionally substituted by one or two C 1-3 -alkyl groups are also suitable for preparing corresponding 2-oxo-morpholin-4-yl derivatives, such as those described in WO 00/55141 or WO 02/18351, for example.
  • Example 2 may be reacted with methyl bromoacetate to form (S)-4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(6-methyl-2-oxo-morpholin-4-yl)ethyloxy]-7-methoxy-quinazoline (cf. Process Example A).
  • the title compound may also be obtained analogously to Method C using (S)-3-[2-(4-toluenesulphonyloxy)ethyl]-5-methyl-oxazolidin-2-one as alkylating agent.
  • the crude product is dissolved in 25 ml of ethyl acetate in the heat, combined with activated charcoal and filtered. The filtrate is combined with 80 ml diisopropylether and cooled to 0° C. The precipitate is suction filtered and dried at 50° C.
  • N,N′-carbonyldiimidazole 89 mg of N,N′-carbonyldiimidazole are added to 217 mg 4-[(3-chloro-4-fluoro-phenyl)amino]-6- ⁇ 2-[(2-hydroxy-2-methyl-propyl)amino]ethyloxy ⁇ -7-methoxy-quinazoline in 4 ml of tetrahydrofuran and stirred for 18 hours at ambient temperature and for a further 6 hours at 70° C. After the addition of another 40 mg N,N′-carbonyldiimidazole the mixture is again stirred for 3 hours at 70° C. The reaction mixture is cooled in the ice bath, the precipitate is suction filtered, washed with a little tetrahydrofuran and dried.
  • Coated tablets containing 75 mg of active substance 1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Preparation:
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate.
  • Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape.
  • the tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film-coated tablets are polished with beeswax.
  • Tablets containing 100 mg of active substance Composition 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Method of Preparation:
  • the active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50° C. it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
  • Weight of tablet 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
  • Tablets containinci 150 mg of active substance Composition: 1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg Preparation:
  • the active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm.
  • the granules, dried at 45° C., are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
  • Hard gelatine capsules containing 150 mg of active substance 1 capsule contains: active substance 150.0 mg corn starch (dried) approx. 80.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg Preparation:
  • the active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus.
  • the finished mixture is packed into size 1 hard gelatine capsules.
  • Capsule filling approx. 320 mg
  • Capsule shell size 1 hard gelatine capsule.
  • Suppositories containing 150 mg of active substance 1 suppository contains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg Preparation:
  • the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
  • Suspension containing 50 mg of active substance 100 ml of suspension contain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml Preparation:
  • the distilled water is heated to 70° C.
  • the methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring.
  • the solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring.
  • the suspension is evacuated with stirring to eliminate air.
  • the active substance is dissolved in the requisite amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
  • the active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
  • Capsules for powder inhalation containing 5 mg of active substance 1 capsule contains: active substance 5.0 mg lactose for inhalation 15.0 mg 20.0 mg Preparation:
  • the active substance is mixed with lactose for inhalation.
  • the mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg).
  • Solution for inhalation for hand-held nebulisers containing 2.5 mg active substance 1 spray contains: active substance 2.500 mg benzalkonium chloride 0.001 mg 1N hydrochloric acid q.s. ethanol/water (50/50) ad 15.000 mg Preparation:
  • the active substance and benzalkonium chloride are dissolved in ethanol/water (50/50).
  • the pH of the solution is adjusted with 1N hydrochloric acid.
  • the resulting solution is filtered and transferred into suitable containers for use in hand-held nebulizers (cartridges).
  • the organic phase is evaporated down at 200 mbar to 50% of the original volume and 4300 ml of n-butyl acetate are added.
  • the mixture is heated to 120–130° C. for 40 hours, filtered and evaporated down to a volume of 2000 ml at 200 mbar. After cooling to ⁇ 10° C. the precipitate is suction filtered, washed with 800 ml n-butyl acetate and dried at 50° C.
  • the crude product is recrystallised twice from methylethylketone (3750 and 5100 ml).

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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
US10/860,453 2003-06-06 2004-06-03 Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them Expired - Lifetime US7196091B2 (en)

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US20050070560A1 (en) * 2003-09-30 2005-03-31 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
US20090036676A1 (en) * 2002-03-30 2009-02-05 Frank Himmelsbach Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20090318480A1 (en) * 2006-09-18 2009-12-24 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
US20100010023A1 (en) * 2000-12-20 2010-01-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20100022505A1 (en) * 2007-02-06 2010-01-28 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
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US20110136805A1 (en) * 2006-11-10 2011-06-09 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same
US20110190248A1 (en) * 2008-08-08 2011-08-04 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
US9089571B2 (en) 2005-11-11 2015-07-28 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
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US7910731B2 (en) 2002-03-30 2011-03-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
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US20090036676A1 (en) * 2002-03-30 2009-02-05 Frank Himmelsbach Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
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AR044604A1 (es) 2005-09-21
UY28347A1 (es) 2005-01-31
EP1641767A2 (de) 2006-04-05
US20060264450A1 (en) 2006-11-23
US20050014772A1 (en) 2005-01-20
US20100267718A1 (en) 2010-10-21
DE10326186A1 (de) 2004-12-23
WO2004108664A3 (de) 2005-05-26
CA2526995A1 (en) 2004-12-16
JP2006527176A (ja) 2006-11-30

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